The Use Of Amido- And Imido-Functionalized Alpha Hydroxy Acids In The Creation Of Biodegradable Polyesters: An Exploration Of Va

The purpose of this thesis was to synthesize biodegradable polyesters from a wide array of functionalized ¿-hydroxy acids. The initial strategy was to use amido-functionalized ¿-hydroxy acids and 2-bromopropanoyl bromide to form amido-functionalized cyclic diesters. Then, the resulting cyclic diesters would be used in ring opening polymerization to create biodegradable polyesters. However, the spontaneous rapid degradation of the secondary amido-functionalized cyclic diester structure, as seen with 2-benzamido-hydroxyacetic acid, limited ring formation to tertiary amido-functionalized ¿-hydroxy acids. Also, the hydrophilic nature of most ¿-hydroxy acids allowed water into the crystal structure of the ¿-hydroxy acid. Then, when the ¿-hydroxy acid was used in ring forming reactions, the associated water deactivated reactive reagents and limited cyclic diester synthesis. These issues led to the synthesis of hydrophobic and tertiary amido- and imido-functionalized ¿-hydroxy acids, 2-phthalimido-2-hydroxyacetic acid and 2-(1-oxoisoindolin-2-yl) hydroxyacetic acid. The new ¿-hydroxy acids were used in two new polymerization techniques, melt polycondensation and solution polymerization, instead of ring open polymerization. Melt polycondensation and solution polymerization had shown previous success in forming oligomers of amido-functionalized ¿-hydroxy acids. Melt polycondensation was conducted by heating the monomer past its melting temperature under reduced pressure. The uncatalyzed melt polycondensation of 2-(1-oxoisoindolin-2-yl) hydroxyacetic acid created polyesters (¿ 960 g/mol). The scandium(III) trifluoromethanesulfonate enhanced melt polycondensation polymerization created slightly larger oligomers (¿ 1340 g/mol). However, 2-phthalimido-2-hydroxyacetic acid was not compatible with melt polycondensation because thermal degradation occurred. Thus, solution polymerization was conducted via Steglich esterification. Only oligomeric functionalized polyesters were formed (¿ 1060 g/mol). Future work should focus on optimization of the catalyst and the reaction conditions to obtain higher molecular weight polyesters. Also, 2-(1-oxoisoindolin-2-yl) hydroxyacetic acid should be utilized in the cyclic diester synthesis technique.

The Crystallization Kinetics of Polylactic Acid (Pla) Processed Through Solid-State/Melt Extrusion

Polylactic acid (PLA) is a bio-derived, biodegradable polymer with a number of similar mechanical properties to commodity plastics like polyethylene (PE) and polyethylene terephthalate (PETE). There has recently been a great interest in using PLA to replace these typical petroleum-derived polymers because of the developing trend to use more sustainable materials and technologies. However, PLA¿s inherent slow crystallization behavior is not compatible with prototypical polymer processing techniques such as molding and extrusion, and in turn inhibits its widespread use in industrial applications. In order to make PLA into a commercially-viable material, there is a need to process the material in such a way that its tendency to form crystals is enhanced. The industry standard for producing PLA products is via twin screw extrusion (TSE), where polymer pellets are fed into a heated extruder, mixed at a temperature above its melting temperature, and molded into a desired shape. A relatively novel processing technique called solid-state shear pulverization (SSSP) processes the polymer in the solid state so that nucleation sites can develop and fast crystallization can occur. SSSP has also been found to enhance the mechanical properties of a material, but its powder output form is undesirable in industry. A new process called solid-state/melt extrusion (SSME), developed at Bucknell University, combines the TSE and SSSP processes in one instrument. This technique has proven to produce moldable polymer products with increased mechanical strength. This thesis first investigated the effects of the TSE, SSSP, and SSME polymer processing techniques on PLA. The study seeks to determine the process that yields products with the most enhanced thermal and mechanical properties. For characterization, percent crystallinity, crystallization half time, storage modulus, softening temperature, degradation temperature and molecular weight were analyzed for all samples. Through these characterization techniques, it was observed that SSME-processed PLA had enhanced properties relative to TSE- and SSSP-processed PLA. Because of the previous findings, an optimization study for SSME-processed PLA was conducted where throughput and screw design were varied. The optimization study determined PLA processed with a low flow rate and a moderate screw design in an SSME process produced a polymer product with the largest increase in thermal properties and a high retention of polymer structure relative to TSE-, SSSP-, and all other SSME-processed PLA. It was concluded that the SSSP part of processing scissions polymer chains, creating defects within the material, while the TSE part of processing allows these defects to be mixed thoroughly throughout the sample. The study showed that a proper SSME setup allows for both the increase in nucleation sites within the polymer and sufficient mixing, which in turn leads to the development of a large amount of crystals in a short period of time.

Myoblast-seeded biodegradable scaffolds to prevent post-myocardial infarction evolution toward heart failure

OBJECTIVE(S): Even though the mechanism is not clearly understood, direct intramyocardial cell transplantation has demonstrated potential to treat patients with severe heart failure. We previously reported on the bioengineering of myoblast-based constructs. We investigate here the functional outcome of infarcted hearts treated by implantation of myoblast-seeded scaffolds. METHODS: Adult Lewis rats with echocardiography-confirmed postinfarction reduced ejection fraction (48.3% +/- 1.1%) were randomized to (1) implantation of myoblast-seeded polyurethane patches at the site of infarction (PU-MyoB, n = 11), (2) implantation of nonseeded polyurethane patches (PU, n = 11), (3) sham operation (Sham, n = 12), and (4) direct intramyocardial myoblast injection (MyoB, n = 11). Four weeks later, the functional assessment by echocardiography was repeated, and we additionally performed left ventricular catheterization plus histologic studies. RESULTS: The ejection fraction significantly decreased in the PU (39.1% +/- 2.3%; P = .02) and Sham (39.9% +/- 3.5%; P = .04) groups, whereas it remained stable in the PU-MyoB (48.4% +/- 3.1%) and MyoB (47.9% +/- 3.0%) groups during the observation time. Similarly, left ventricular contractility was significantly higher in groups PU-MyoB (4960 +/- 266 mm Hg/s) and MyoB (4748 +/- 304 mm Hg/s) than in groups PU (3909 +/- 248 mm Hg/s, P = .01) and Sham (4028 +/- 199 mm Hg/s, P = .01). Immunohistology identified a high density of myoblasts within the seeded scaffolds without any migration toward the host cardiac tissue and no evidence of cardiac cell differentiation. CONCLUSIONS: Myoblast-seeded polyurethane scaffolds prevent post-myocardial infarction progression toward heart failure as efficiently as direct intramyocardial injection. The immunohistologic analysis suggests that an indirect mechanism, potentially a paracrine effect, may be assumed.

Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation (LEADERS): a randomised non-inferiority trial

BACKGROUND: A novel stent platform eluting biolimus, a sirolimus analogue, from a biodegradable polymer showed promising results in preliminary studies. We compared the safety and efficacy of a biolimus-eluting stent (with biodegradable polymer) with a sirolimus-eluting stent (with durable polymer). METHODS: We undertook a multicentre, assessor-blind, non-inferiority study in ten European centres. 1707 patients aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes were centrally randomised by a computer-generated allocation sequence to treatment with either biolimus-eluting (n=857) or sirolimus-eluting (n=850) stents. The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation within 9 months. Analysis was by intention to treat. 427 patients were randomly allocated to angiographic follow-up, with in-stent percentage diameter stenosis as principal outcome measure at 9 months. The trial is registered with ClinicalTrials.gov, number NCT00389220. FINDINGS: We analysed all randomised patients. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents for the primary endpoint at 9 months (79 [9%] patients vs 89 [11%], rate ratio 0.88 [95% CI 0.64-1.19], p for non-inferiority=0.003, p for superiority=0.39). Frequency of cardiac death (14 [1.6%] vs 21 [2.5%], p for superiority=0.22), myocardial infarction (49 [5.7%] vs 39 [4.6%], p=0.30), and clinically-indicated target vessel revascularisation (38 [4.4%] vs 47 [5.5%], p=0.29) were similar for both stent types. 168 (79%) patients in the biolimus-eluting group and 167 (78%) in the sirolimus-eluting group had data for angiographic follow-up available. Biolimus-eluting stents were non-inferior to sirolimus-eluting stents in in-stent percentage diameter stenosis (20.9%vs 23.3%, difference -2.2% [95% CI -6.0 to 1.6], p for non-inferiority=0.001, p for superiority=0.26). INTERPRETATION: Our results suggest that a stent eluting biolimus from a biodegradable polymer represents a safe and effective alternative to a stent eluting sirolimus from a durable polymer in patients with chronic stable coronary artery disease or acute coronary syndromes. FUNDING: Biosensors Europe SA, Switzerland.

Screening, optimization and extraction of polyhydroxyalkanoates and peptidoglycan from Bacillus megaterium

Bioplastics are polymers (such as polyesters) produced from bacterial fermentations that are biodegradable and nonhazardous. They are produced by a wide variety of bacteria and are made only when stress conditions allow, such as when nutrient levels are low, more specifically levels of nitrogen and oxygen. These stress conditions cause certain bacteria to build up excess carbon deposits as energy reserves in the form of polyhydroxyalkanoates (PHAs). PHAs can be extracted and formed into actual plastic with the same strength of conventional, synthetic-based plastics without the need to rely on foreign petroleum. The overall goal of this project was to select for a bacteria that could grow on sugars found in the lignocellulosic biomass, and get the bacteria to produce PHAs and peptidoglycan. Once this was accomplished the goal was to extract PHAs and peptidoglycan in order to make a stronger more rigid plastic, by combing them into a co-polymer. The individual goals of this project were to: (1) Select and screen bacteria that are capable of producing PHAs by utilizing the carbon/energy sources found in lignocellulosic biomass; (2) Maximize the utilization of those sugars present in woody biomass in order to produce optimal levels of PHAs. (3) Use room temperature ionic liquids (RTILs) in order to separate the cell membrane and peptidoglycan, allowing for better extraction of PHAs and more intact peptidoglycan. B. megaterium a Gram-positive PHA-producing bacterium was selected for study in this project. It was grown on a variety of different substrates in order to maximize both its growth and production of PHAs. The optimal conditions were found to be 30°C, pH 6.0 and sugar concentration of either 30g/L glucose or xylose. After optimal growth was obtained, both RTILs and enzymatic treatments were used to break the cell wall, in order to extract the PHAs, and peptidoglycan. PHAs and peptidoglycan were successfully extracted from the cell, and will be used in the future to create a new stronger co-polymer. Peptidoglycan recovery yield was 16% of the cells’ dry weight.

Impact of vessel size on angiographic and clinical outcomes of revascularization with biolimus-eluting stent with biodegradable polymer and sirolimus-eluting stent with durable polymer the LEADERS trial substudy

OBJECTIVES: We assessed the impact of vessel size on outcomes of stenting with biolimus-eluting degradable polymer stent (BES) and sirolimus-eluting permanent polymer stent (SES) within a randomized multicenter trial (LEADERS). BACKGROUND: Stenting of small vessels might be associated with higher rates of adverse events. METHODS: "All-comer" patients (n = 1,707) were randomized to BES and SES. Post-hoc-stratified analysis of angiographic and clinical outcomes at 9 months and 1 year, respectively, was performed for vessels with reference diameter 2.75 mm. RESULTS: Of 1,707 patients, 429 patients in the BES group with 576 lesions and 434 patients in the SES group with 557 lesions had only small vessels treated (50.6% of the patient cohort). In patients with small vessels there was no significant difference in overall major adverse cardiac events (MACE) rate (12.1% vs. 11.8%; p = 0.89) or target lesion revascularization (TLR) rate (9.6% vs. 7.4%; p = 0.26) between BES and SES. The MACE and TLR rates in the small-vessel patient population were higher than in the large-vessel population. The TLR rate was 9.6% versus 2.6%, and MACE rate was 12.1% versus 7.1% for small versus large vessels in the BES arm (TLR: hazard ratio [HR] = 3.724, p = 0.0013; MACE: HR = 1.720, p = 0.0412). In the SES arm, TLR was 7.4% versus 5.1%, and MACE was 11.8% versus 10.3% in small versus large vessels (TLR: HR = 1.435, p = 0.2594; MACE: HR = 1.149, p = 0.5546). CONCLUSIONS: Prevalence of small vessel disease is high in an "all-comer" population with higher TLR and MACE rates. The BES and SES seem equivalent in treatment outcomes of small vessels in this "all-comer" patient population.

Biolimus-eluting biodegradable polymer versus sirolimus-eluting permanent polymer stent performance in long lesions: results from the LEADERS multicentre trial substudy

AIMS: Lesion length remains a predictor of target lesion revascularisation and results of long lesion stenting remain poor. Sirolimus-eluting stents have been shown to perform better than paclitaxel eluting stents in long lesions. In this substudy of the LEADERS trial, we compared the performance of biolimus biodegradable polymer (BES) and sirolimus permanent polymer stents (SES) in long lesions. METHODS AND RESULTS: A total of 1,707 'all-comer' patients were randomly allocated to treatment with BES and SES. A stratified analysis of angiographic and clinical outcomes at nine months and one year, respectively was performed for vessels with lesion length <20 mm versus >20 mm (as measured by quantitative angiography).Of 1,707 patients, 592 BES patients with 831 lesions and 619 SES patients with 876 lesions had only short lesions treated. One hundred and fifty-three BES patients with 166 lesions and 151 SES patients with 162 lesions had long lesions. There were no significant differences in baseline clinical characteristics, except for higher number of patients with long lesions presenting with acute myocardial infarction in both stent groups. Long lesions tended to have lower MLD and greater percent diameter stenosis at baseline than short lesions. Late loss was greater for long lesions than short lesions. There was no statistically significant difference in late loss between BES and SES stents (0.32+/-0.69 vs 0.24+/-0.57, p=0.59). Binary in-segment restenosis was present in 23.2% versus 13.1% of long lesions treated with BES and SES, respectively (p=0.042). In patients with long lesions, the overall MACE rate was similar for BES and SES (17% vs 14.6%; p=0.62). There was a trend towards higher overall TLR rate with BES (12.4 % vs 6.0%; HR=2.06; p=0.07) and clinically driven TLR (10.5% vs 5.3%: HR 1.94; p=0.13). Rates of definite stent thrombosis were 3.3% in the long lesion group and 1.3-1.7 % in the short lesion group. CONCLUSIONS: BES and SES appear similar with respect to MACE in long lesions in this "all-comer" patient population. However, long lesions tended to have a higher rate of binary in-segment restenosis and TLR following BES than SES treatment.

A feasibility study evaluating an in situ formed synthetic biodegradable membrane for guided bone regeneration in dogs

PURPOSE: The aim was (1) to evaluate the soft-tissue reaction of a synthetic polyethylene glycol (PEG) hydrogel used as a barrier membrane for guided bone regeneration (GBR) compared with a collagen membrane and (2) to test whether or not the application of this in situ formed membrane will result in a similar amount of bone regeneration as the use of a collagen membrane. MATERIAL AND METHODS: Tooth extraction and preparation of osseous defects were performed in the mandibles of 11 beagle dogs. After 3 months, 44 cylindrical implants were placed within healed dehiscence-type bone defects resulting in approximately 6 mm exposed implant surface. The following four treatment modalities were randomly allocated: PEG+autogenous bone chips, PEG+hydroxyapatite (HA)/tricalcium phosphate (TCP) granules, bioresorbable collagen membrane+autogenous bone chips and autogenous bone chips without a membrane. After 2 and 6 months, six and five dogs were sacrificed, respectively. A semi-quantitative evaluation of the local tolerance and a histomorphometric analysis were performed. For statistical analysis, repeated measures analysis of variance (ANOVA) and subsequent pairwise Student's t-test were applied (P<0.05). RESULTS: No local adverse effects in association with the PEG compared with the collagen membrane was observed clinically and histologically at any time-point. Healing was uneventful and all implants were histologically integrated. Four out of 22 PEG membrane sites revealed a soft-tissue dehiscence after 1-2 weeks that subsequently healed uneventful. Histomorphometric measurement of the vertical bone gain showed after 2 months values between 31% and 45% and after 6 months between 31% and 38%. Bone-to-implant contact (BIC) within the former defect area was similarly high in all groups ranging from 71% to 82% after 2 months and 49% to 91% after 6 months. However, with regard to all evaluated parameters, the PEG and the collagen membranes did not show any statistically significant difference compared with sites treated with autogenous bone without a membrane. CONCLUSION: The in situ forming synthetic membrane made of PEG was safely used in the present study, revealing no biologically significant abnormal soft-tissue reaction and demonstrated similar amounts of newly formed bone for defects treated with the PEG membrane compared with defects treated with a standard collagen membrane.

Long-term outcomes of biodegradable polymer versus durable polymer drug-eluting stents in patients with diabetes a pooled analysis of individual patient data from 3 randomized trials

BACKGROUND There is ongoing debate on the optimal drug-eluting stent (DES) in diabetic patients with coronary artery disease. Biodegradable polymer drug-eluting stents (BP-DES) may potentially improve clinical outcomes in these high-risk patients. We sought to compare long-term outcomes in patients with diabetes treated with biodegradable polymer DES vs. durable polymer sirolimus-eluting stents (SES). METHODS We pooled individual patient-level data from 3 randomized clinical trials (ISAR-TEST 3, ISAR-TEST 4 and LEADERS) comparing biodegradable polymer DES with durable polymer SES. Clinical outcomes out to 4years were assessed. The primary end point was the composite of cardiac death, myocardial infarction and target-lesion revascularization. Secondary end points were target lesion revascularization and definite or probable stent thrombosis. RESULTS Of 1094 patients with diabetes included in the present analysis, 657 received biodegradable polymer DES and 437 durable polymer SES. At 4years, the incidence of the primary end point was similar with BP-DES versus SES (hazard ratio=0.95, 95% CI=0.74-1.21, P=0.67). Target lesion revascularization was also comparable between the groups (hazard ratio=0.89, 95% CI=0.65-1.22, P=0.47). Definite or probable stent thrombosis was significantly reduced among patients treated with BP-DES (hazard ratio=0.52, 95% CI=0.28-0.96, P=0.04), a difference driven by significantly lower stent thrombosis rates with BP-DES between 1 and 4years (hazard ratio=0.15, 95% CI=0.03-0.70, P=0.02). CONCLUSIONS In patients with diabetes, biodegradable polymer DES, compared to durable polymer SES, were associated with comparable overall clinical outcomes during follow-up to 4years. Rates of stent thrombosis were significantly lower with BP-DES.

Improved safety and reduction in stent thrombosis associated with biodegradable polymer-based biolimus-eluting stents versus durable polymer-based sirolimus-eluting stents in patients with coronary artery disease: final 5-year report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) randomized, noninferiority trial

OBJECTIVES This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. BACKGROUND The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. METHODS The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N = 1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n = 857) or durable polymer sirolimus-eluting stents (SES) (n = 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. RESULTS At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, p for superiority = 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority = 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n = 5 [0.7%] vs. n = 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p = 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n = 3 of 749 vs. n = 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p = 0.005). CONCLUSIONS The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220).

Long-term outcomes of biodegradable versus durable polymer drug-eluting stents in patients with acute ST-segment elevation myocardial infarction: a pooled analysis of individual patient data from three randomised trials

Aims: Arterial plaque rupture and thrombus characterise ST-elevation myocardial infarction (STEMI) and may aggravate delayed arterial healing following durable polymer drug-eluting stent (DP-DES) implantation. Biodegradable polymer (BP) may improve biocompatibility. We compared long-term outcomes in STEMI patients receiving BP-DES vs. durable polymer sirolimus-eluting stents (DP-SES). Methods and results: We pooled individual patient-level data from three randomised clinical trials (ISAR-TEST-3, ISAR-TEST-4 and LEADERS) comparing outcomes from BP-DES with DP-SES at four years. The primary endpoint (MACE) comprised cardiac death, MI, or target lesion revascularisation (TLR). Secondary endpoints were TLR, cardiac death or MI, and definite or probable stent thrombosis. Of 497 patients with STEMI, 291 received BP-DES and 206 DP-SES. At four years, MACE was significantly reduced following treatment with BP-DES (hazard ratio [HR] 0.59, 95% CI: 0.39-0.90; p=0.01) driven by reduced TLR (HR 0.54, 95% CI: 0.30-0.98; p=0.04). Trends towards reduction were seen for cardiac death or MI (HR 0.63, 95% CI: 0.37-1.05; p=0.07) and definite or probable stent thrombosis (3.6% vs. 7.1%; HR 0.49, 95% CI: 0.22-1.11; p=0.09). Conclusions: In STEMI, BP-DES demonstrated superior clinical outcomes to DP-SES at four years. Trends towards reduced cardiac death or myocardial infarction and reduced stent thrombosis require corroboration in specifically powered trials.

Randomized comparison of biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for percutaneous coronary revascularization: Rationale and design of the BIOSCIENCE trial

Background Biodegradable polymers for release of antiproliferative drugs from metallic drug-eluting stents (DES) aim to improve long-term vascular healing and efficacy. We designed a large scale clinical trial to compare a novel thin strut, cobalt chromium DES with silicon carbide coating releasing sirolimus from a biodegradable polymer (Orsiro, O-SES) with the durable polymer-based Xience Prime everolimus-eluting stent (X-EES) in an all-comers patient population. Design The multicenter BIOSCIENCE trial (NCT01443104) randomly assigned 2,119 patients to treatment with biodegradable polymer SES or durable polymer EES at 9 sites in Switzerland. Patients with chronic stable coronary artery disease or acute coronary syndromes, including non-ST-elevation and ST-elevation myocardial infarction, were eligible for the trial if they had at least one lesion with a diameter stenosis >50% appropriate for coronary stent implantation. The primary endpoint target lesion failure (TLF) is a composite of cardiac death, target-vessel myocardial infarction, and clinically-driven target lesion revascularization within 12 months. Assuming a TLF rate of 8% at 12 months in both treatment arms and accepting 3.5% as a margin for non-inferiority, inclusion of 2,060 patients would provide 80% power to detect non-inferiority of the biodegradable polymer SES compared with the durable polymer EES at a one-sided type I error of 0.05. Clinical follow-up will be continued through five years. Conclusion The BIOSCIENCE trial will determine whether the biodegradable polymer SES is non-inferior to the durable polymer EES with respect to TLF.

Biolimus-Eluting Stents With Biodegradable Polymer Versus Bare-Metal Stents in Acute Myocardial Infarction: Two-Year Clinical Results of the COMFORTABLE AMI Trial

BACKGROUND This study sought to determine whether the 1-year differences in major adverse cardiac event between a stent eluting biolimus from a biodegradable polymer and bare-metal stents (BMSs) in the COMFORTABLE trial (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction) were sustained during long-term follow-up. METHODS AND RESULTS A total of 1061 patients were randomly assigned to biolimus-eluting stent (BES) and BMS at 11 centers, and follow-up rates at 2 years were 96.3%. A subgroup of 103 patients underwent angiography at 13 months. At 2 years, differences in the primary end point of cardiac death, target-vessel myocardial infarction, and target lesion revascularization continued to diverge in favor of BES-treated patients (5.8%) compared with BMS-treated patients (11.9%; hazard ratio=0.48; 95% confidence interval, 0.31-0.72; P<0.001) with a significant risk reduction during the second year of follow-up (hazard ratio 1-2 years=0.45; 95% confidence interval, 0.20-1.00; P=0.049). Differences in the primary end point were driven by a reduction in target lesion revascularization (3.1% versus 8.2%; P<0.001) and target-vessel reinfarction (1.3% versus 3.4%; P=0.023). The composite of death, any reinfarction and revascularization (14.5% versus 19.3%; P=0.03), and cardiac death or target-vessel myocardial infarction (4.2% versus 7.2%; P=0.036) were less frequent among BES-treated patients compared with BMS-treated patients. The 13-month angiographic in-stent percent diameter stenosis amounted to 12.0±7.2 in BES- and 39.6±25.2 in BMS-treated lesions (P<0.001). CONCLUSIONS Among patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, BES continued to improve cardiovascular events compared with BMS beyond 1 year.

Ultrathin strut biodegradable polymer sirolimus-eluting stent versus durable polymer everolimus-eluting stent for percutaneous coronary revascularisation (BIOSCIENCE): a randomised, single-blind, non-inferiority trial

BACKGROUND Refinements in stent design affecting strut thickness, surface polymer, and drug release have improved clinical outcomes of drug-eluting stents. We aimed to compare the safety and efficacy of a novel, ultrathin strut cobalt-chromium stent releasing sirolimus from a biodegradable polymer with a thin strut durable polymer everolimus-eluting stent. METHODS We did a randomised, single-blind, non-inferiority trial with minimum exclusion criteria at nine hospitals in Switzerland. We randomly assigned (1:1) patients aged 18 years or older with chronic stable coronary artery disease or acute coronary syndromes undergoing percutaneous coronary intervention to treatment with biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Randomisation was via a central web-based system and stratified by centre and presence of ST segment elevation myocardial infarction. Patients and outcome assessors were masked to treatment allocation, but treating physicians were not. The primary endpoint, target lesion failure, was a composite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularisation at 12 months. A margin of 3·5% was defined for non-inferiority of the biodegradable polymer sirolimus-eluting stent compared with the durable polymer everolimus-eluting stent. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01443104. FINDINGS Between Feb 24, 2012, and May 22, 2013, we randomly assigned 2119 patients with 3139 lesions to treatment with sirolimus-eluting stents (1063 patients, 1594 lesions) or everolimus-eluting stents (1056 patients, 1545 lesions). 407 (19%) patients presented with ST-segment elevation myocardial infarction. Target lesion failure with biodegradable polymer sirolimus-eluting stents (69 cases; 6·5%) was non-inferior to durable polymer everolimus-eluting stents (70 cases; 6·6%) at 12 months (absolute risk difference -0·14%, upper limit of one-sided 95% CI 1·97%, p for non-inferiority <0·0004). No significant differences were noted in rates of definite stent thrombosis (9 [0·9%] vs 4 [0·4%], rate ratio [RR] 2·26, 95% CI 0·70-7·33, p=0·16). In pre-specified stratified analyses of the primary endpoint, biodegradable polymer sirolimus-eluting stents were associated with improved outcome compared with durable polymer everolimus-eluting stents in the subgroup of patients with ST-segment elevation myocardial infarction (7 [3·3%] vs 17 [8·7%], RR 0·38, 95% CI 0·16-0·91, p=0·024, p for interaction=0·014). INTERPRETATION In a patient population with minimum exclusion criteria and high adherence to dual antiplatelet therapy, biodegradable polymer sirolimus-eluting stents were non-inferior to durable polymer everolimus-eluting stents for the combined safety and efficacy outcome target lesion failure at 12 months. The noted benefit in the subgroup of patients with ST-segment elevation myocardial infarction needs further study. FUNDING Clinical Trials Unit, University of Bern, and Biotronik, Bülach, Switzerland.

Biolimus-eluting stent with biodegradable polymer improves clinical outcomes in patients with acute myocardial infarction

OBJECTIVE To investigate clinical outcomes of coronary intervention using a biolimus-eluting stent (BES) compared with a sirolimus-eluting stent (SES) in patients with acute myocardial infarction (AMI) in the Limus Eluted from A Durable versus ERodable Stent (LEADERS) coating trial at the final 5-year follow-up. METHODS The LEADERS trial is a multicentre all-comer study, where patients (n=1707) were randomised to percutaneous intervention with either BES containing biodegradable polymer or SES containing durable polymer. Out of 1707 patients enrolled in this trial, 573 patients had percutaneous coronary intervention for AMI (BES=280, SES=293) and were included in the current analysis. Patient-oriented composite endpoint (POCE, including all death, all myocardial infarction (MI) and all revascularisations), major adverse cardiac events (MACE, including cardiac death, MI and clinically indicated target vessel revascularisation) and stent thrombosis were assessed at 5-year follow-up. RESULTS The baseline clinical, angiographic and procedural characteristics were well matched between BES and SES groups. In all patients with AMI, coronary intervention with a BES, compared with SES, significantly reduced POCE (28.9% vs 42.3%; relative risk (RR) 0.61, 95% CI 0.47 to 0.82, p=0.001) at 5-year follow-up. There was also a reduction in MACE rate in the BES group (18.2% vs 25.9%; RR 0.67, 95% CI 0.47 to 0.95, p=0.025); however, there was no difference in cardiac death and stent thrombosis. In patients with ST-elevation MI (STEMI), coronary intervention with BES significantly reduced POCE (24.4% vs 39.3%; RR 0.55, 95% CI 0.36 to 0.85, p=0.006), MACE (12.6% vs 25.0%; RR 0.47, 95% CI 0.26 to 0.83, p=0.008) and cardiac death (3.0% vs 11.4%; RR 0.25, 95% CI 0.08 to 0.75, p=0.007), along with a trend towards reduction in definite stent thrombosis (3.7% vs 8.6%; RR 0.41, 95% CI 0.15 to 1.18, p=0.088), compared with SES. CONCLUSIONS BES, compared with SES, significantly improved safety and efficacy outcomes in patients with AMI, especially those with STEMI, at 5-year follow-up. TRIAL REGISTRATION NUMBER NCT 00389220.